Allosteric chromenone inhibitors of phosphoinositide 3-kinase (pi3k) for the treatment of disease

ABSTRACT

The disclosure relates to compounds of Formula (I) as allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) useful in the treatment of diseases or disorders associated with PI3K modulation, Formula (I):or pharmaceutically acceptable salts thereof wherein R, R1, R2, R3, R4, R5, R6, R7, and R8, are as defined herein. The disclosure also relates to methods of making and using compounds of Formula (I) or pharmaceutically acceptable salts thereof.

FIELD

The present invention is directed to allosteric chromenone inhibitors ofphosphoinositide 3-kinase (PI3K) useful in the treatment of diseases, ordisorders associated with PI3K modulation. The invention is directedtoward compounds, and compositions which inhibit PI3K, methods of (oruses for) treating a disease, or disorder associated with PI3K (e.g.,CLOVES syndrome (congenital lipomatous overgrowth, vascularmalformations, epidermal naevi, scoliosis/skeletal and spinal syndrome),PIK3CA-related overgrowth syndrome (PROS), breast cancer, brain cancer,prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma,sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, orhead and neck cancer), and using, or methods of using, PI3K inhibitorsin combination with one or more additional cancer therapies.

BACKGROUND

The activity of cells can be regulated by external signals thatstimulate, or inhibit intracellular events. The process by whichstimulatory, or inhibitory signals are transmitted into, and within acell to elicit an intracellular response is referred to as signaltransduction. Over the past decades, cascades of signal transductionevents have been elucidated, and found to play a central role in avariety of biological responses. Defects in various components of signaltransduction pathways have been found to account for a vast number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular, and neuronal diseases (Gaestel et al.Current Medicinal Chemistry (2007) 14:2214-2234).

Kinases represent a class of important signaling molecules. Kinases cangenerally be classified into protein kinases, lipid kinases, and certainkinases exhibiting dual specificities. Protein kinases are enzymes thatphosphorylate other proteins and/or themselves (i.e.,autophosphorylation). Protein kinases can be generally classified intothree major groups based upon their substrate utilization: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src,abl), serine/threonine kinases which predominantly phosphorylatesubstrates on serine and/or threonine residues (e.g., mTorC1, mTorC2,ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylatesubstrates on tyrosine, serine and/or threonine residues.

Lipid kinases are enzymes that catalyze the phosphorylation of lipidswithin cells. These enzymes, and the resulting phosphorylated lipids,and lipid-derived biologically active organic molecules, play a role inmany different physiological processes, including cell proliferation,migration, adhesion, and differentiation. A particular group of lipidkinases comprises membrane lipid kinases, i.e., kinases that catalyzethe phosphorylation of lipids contained in, or associated with cellmembranes. Examples of such enzymes include phosphoinositide(s) kinases(such as PI3-kinases, PI4-Kinases), diacylglycerol kinases, andsphingosine kinases.

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of themost highly mutated systems in human cancers. PI3K signaling is involvedin many other disease states including allergic contact dermatitis,rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases,chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis,asthma, disorders related to diabetic complications, and inflammatorycomplications of the cardiovascular system such as acute coronarysyndrome.

PI3Ks are members of a unique, and conserved family of intracellularlipid kinases that phosphorylate the 3′-OH group onphosphatidylinositols, or phosphoinositides. The PI3K family comprises15 kinases with distinct substrate specificities, expression patterns,and modes of regulation (Katso et al., Annu Rev Cell Dev Biol. 2001;17:615-75). The class I PI3Ks (p110α, p110β, p110δ, and p110γ) aretypically activated by tyrosine kinases, or G-protein coupled receptorsto generate PIP3, which engages downstream effectors such as those inthe pathways of Akt/PDK1, mTOR, the Tec family kinases, and the Rhofamily GTPases. The class II, and III PI3Ks play a key role inintracellular trafficking through the synthesis of PI(3)P, andPI(3,4)P₂.

The PI3K isoforms have been implicated, for example, in a variety ofhuman cancers, and disorders. Mutations in the gene coding for PI3Kisoforms, or mutations which lead to upregulation of a PI3K isoform arebelieved to occur in many human cancers. Mutations in the gene codingfor a PI3K isoform are point mutations clustered within several hotspotsin helical, and kinase domains. Because of the high rate of PI3Kmutations, targeting of this pathway may provide valuable therapeuticopportunities.

Genetic alterations in genes in PI3K signaling are believed to beinvolved in a range of cancers such as endometrial cancer, breastcancer, esophageal squamous-cell cancer, cervical squamous-cellcarcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladderurothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lungcancer, esophagogastric cancer, nerve-sheath tumor, head and necksquamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma,soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma,hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreaticcancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma,adrenocortical carcinoma, renal non-clear-cell carcinoma, renalclear-cell carcinoma, germ-cell carcinoma, thymic tumor,pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer,leukemia, and encapsulated glioma (Goncalves M D, Hopkins B D, Cantley LC. Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl JMed. 2018 Nov. 22; 379(21):2052-2062).

The alpha (α) isoform of PI3K has been implicated, for example, in avariety of human cancers. Angiogenesis has been shown to selectivelyrequire the a isoform of PI3K in the control of endothelial cellmigration. (Graupera et al, Nature 2008; 453; 662-6). Mutations in thegene coding for PI3Kα, or mutations which lead to upregulation of PI3Kαare believed to occur in many human cancers such as lung, stomach,endometrial, ovarian, bladder, breast, colon, brain, prostate, and skincancers. Mutations in the gene coding for PI3Kα are point mutationsclustered within several hotspots in helical, and kinase domains, suchas E542K, E545K, and H1047R. Many of these mutations have been shown tobe oncogenic gain-of-function mutations. Because of the high rate ofPI3Kα mutations, targeting of this pathway may provide valuabletherapeutic opportunities. While other PI3K isoforms such as PI3Kδ, orPI3Kγ are expressed primarily in hematopoietic cells, PI3Kα, along withPI3Kβ, is expressed constitutively.

Mutated PI3Kα has been implicated in brain metastases in HR+/HER2−metastatic breast cancers. Development of brain-penetrant PI3Kαinhibitors may provide improved therapeutic benefit over current PI3Kαinhibitors. (Fitzgerald et al., Association between PIK3CA mutationstatus and development of brain metastases in HR+/HER2− metastaticbreast cancer. Ann Oncol 30:v110, 2019 (suppl 5)).

Due to the central role of PI3Kα in regulating organismal glucosehomeostasis, PI3K inhibition in patients often gives rise tohyperglycemia and/or hyperinsulinemia (Busaidy N L, et al, Management ofmetabolic effects associated with anticancer agents targeting thePI3K-Akt-mTOR pathway. J Clin Oncol 2012; 30:2919-28). High levels ofcirculating insulin could potentially be mitogenic and/or antiapoptoticfor cancer cells, and thus negate the antiproliferative effects of PI3Kinhibitors (Blouin M-J, et al, Abstract 4615: The hyperinsulinemiacaused by PI3K inhibitors attenuates their antineoplastic efficacy, butcan be minimized by co-administration of metformin. Cancer Res 2013;73:4615).

In the setting of cancer with mutated PI3Kα, one way to overcome theproblem of compensatory production of insulin and/or glucose uponsystemic PI3Kα inhibition would be to develop inhibitors with enhancedselectivity for mutant PI3Kα over wild-type PI3Kα. This would create anincreased window for drug dosing to selectively inhibit the pathologicsignaling of mutant PI3Kα in the cancer cells without affecting thewild-type PI3Kα in the host tissues that control systemic metabolism(Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in Cancer:Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, andImmunotherapy. Cancer Discov. 2016 October; 6(10):1090-1105), thuslimiting toxicities, and permitting higher doses, and more completeinhibition of the drug target (Ariella B. Hanker, et al, Challenges forthe clinical development of PI3K inhibitors: Strategies to improve theirimpact in solid tumors. Cancer Discov. 2019 April; 9(4): 482-491).

Currently PI3Kα inhibitors are nearly equipotent to wild-type, andmutant PI3Kα. Mutant selective inhibitors have been elusive due to thePI3Kα mutations location far from the active site. As such, inhibitorswhich target a second, peripheral binding pocket near a known mutation(e.g., H1047R) may provide a route to selective PI3Kα inhibition. Thus,targeting a mutated, peripheral binding pocket of PI3Kα, provides avaluable therapeutic target for drug development.

As such, kinases, for example lipid kinases such as PI3Ks, are primetargets for drug development. The present invention provides a new classof kinase inhibitors.

SUMMARY

In one aspect, the present invention relates to compounds of Formula(I):

or pharmaceutically acceptable salts thereof, wherein:

R is —H or C₁-C₃ alkyl;

R₁ is a group of the formula:

R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

R₃ is —H, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₅ cycloalkyl,a heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ringheteroatoms independently selected from N, O, or S, or a heteroaryl of 5ring atoms containing 1, 2, or 3 ring heteroatoms independently selectedfrom N, O, or S;

each of R₄, R₅ and R₆ is independently —H, halogen, C₁-C₆ alkyl or C₁-C₆haloalkyl;

R₇ is —CN, C₁-C₆ alkyl or C₁-C₆ haloalkyl;

R₈ is —H or C₆ alkyl;

each R₉ is independently —H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₃-C₅ cycloalkyl;

each R₁₀ is independently —H, —CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,—OH, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₂-C₆ alkenyl, an optionally substituted C₂-C₆ alkynyl, an optionallysubstituted C₃-C₅ cycloalkyl, an optionally substituted heterocycleselected from pyrrolidine, pyrrolidinone, piperidine or morpholine, anoptionally substituted phenyl, an optionally substituted1,3-benzodioxole, an optionally substituted2,3-dihydro-1,4-benzodioxine, or an optionally substituted heteroarylselected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, orthiazole; wherein the optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl,or C₂-C₆ alkynyl is each optionally substituted with a —CN, —OH,oxetanyl, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅ cycloalkyl,phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle orheteroaryl is each optionally substituted with one to three substituentseach independently selected from halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl,C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, —OH or —CN; and

each R₁₁ is independently —H or C₁-C₃ alkyl.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent, or carrier.

In another aspect, the present invention provides a method of modulatingPI3K (e.g., PI3Kα) activity (e.g., in vitro, or in vivo), comprisingcontacting a cell with a therapeutically effective amount of a compoundof Formula (I), (II), or (III), or a pharmaceutically acceptable saltthereof.

In some aspects, the present invention provides a method of treating, orpreventing a disease, or disorder disclosed herein in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt thereof.

In some aspects, the present invention provides a method of treating, orpreventing a disease, or disorder disclosed herein in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof.

In some aspects, the present invention provides a method of treating adisease, or disorder disclosed herein in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt thereof.

In some aspects, the present invention provides a method of treating adisease, or disorder disclosed herein in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition of a compound of Formula (I),(II), or (III), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in therapy.

In another aspect, the present invention provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro, or invivo).

In another aspect, the present invention provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof, foruse in selective inhibition for mutant PI3Kα over wild-type PI3Kα.

In another aspect, the present invention provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof, foruse in treating, or preventing a disease, or disorder disclosed herein.

In another aspect, the present invention provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof, foruse in treating a disease, or disorder disclosed herein.

In another aspect, the present invention provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for modulating PI3K (e.g.,PI3Kα) activity (e.g., in vitro, or in vivo).

In another aspect, the present invention provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for treating, or preventinga disease, or disorder disclosed herein.

In another aspect, the present invention provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for treating a disease, ordisorder disclosed herein.

In another aspect, the present invention provides a method of preparinga compound of Formula (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present invention provides a method of preparinga compound, comprising one, or more steps described herein.

In another aspect, the present invention provides a compound obtainableby, or obtained by, a method for preparing a compound as describedherein (e.g., a method comprising one, or more steps described in theSchemes).

In another aspect, the present invention provides an intermediate asdescribed herein, being suitable for use in a method for preparing acompound as described herein (e.g., the intermediate is selected fromthe intermediates described in the Examples).

Other features, and advantages of the invention will be apparent fromthe following detailed description, and claims.

DETAILED DESCRIPTION

The present invention provides methods of treating, preventing, orameliorating a disease, or disorder, (or uses in the treatment,prevention, or amelioration of a disease, or disorder), in which PI3Kplays a role by administering to a patient in need thereof atherapeutically effective amount of a PI3K inhibitor of the presentinvention. The methods (or uses) of the present invention can be used inthe treatment of a variety of PI3K-dependent diseases, and disorders.

In some embodiments, the disease, or disorder is a cancer (e.g., breastcancer, brain cancers, prostate cancer, endometrial cancer, gastriccancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer,ovarian cancer, skin cancer, or head and neck cancer). In someembodiments, the disease, or disorder associated with PI3K includes, butis not limited to, CLOVES syndrome (congenital lipomatous overgrowth,vascular malformations, epidermal naevi, scoliosis/skeletal, and spinalsyndrome), PIK3CA-related overgrowth syndrome (PROS), endometrialcancer, breast cancer, esophageal squamous-cell cancer, cervicalsquamous-cell carcinoma, cervical adenocarcinoma, colorectaladenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovariancancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheathtumor, head and neck squamous-cell carcinoma, melanoma, esophagogastricadenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellarcarcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer,pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma,adrenocortical carcinoma, renal non-clear-cell carcinoma, renalclear-cell carcinoma, germ-cell carcinoma, thymic tumor,pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer,leukemia, and encapsulated glioma.

The details of the invention are set forth in the accompanyingdescription below. Although methods, and materials similar, orequivalent to those described herein can be used in the practice, ortesting of the present disclosure, illustrative methods, and materialsare now described. Other features, objects, and advantages of theinvention will be apparent from the description, and from the claims. Inthe specification, and the appended claims, the singular forms alsoinclude the plural unless the context clearly dictates otherwise. Unlessdefined otherwise, all technical, and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. All patents, and publications citedin this specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a”, and “an” refer to one, or more than one (i.e., to atleast one) of the grammatical object of the article. By way of example,“an element” means one element, or more than one element.

The term “and/or” means either “and”, or “or” unless indicatedotherwise.

The term “administer”, “administering”, or “administration” refers toeither directly administering a disclosed compound, or pharmaceuticallyacceptable salt of the disclosed compound, or a composition to asubject.

The term “alkenyl” refers to a straight, or branched chain unsaturatedhydrocarbon containing 2-12 carbon atoms. The “alkenyl” group containsat least one double bond in the chain. The double bond of an alkenylgroup can be unconjugated, or conjugated to another unsaturated group.Examples of alkenyl groups include ethenyl, propenyl, n-butenyl,iso-butenyl, pentenyl, or hexenyl.

The term “alkoxy” refers to a straight, or branched chain saturatedhydrocarbon containing 1-12 carbon atoms containing a terminal “O” inthe chain, i.e., —O(alkyl). Examples of alkoxy groups include withoutlimitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxygroups.

The term “alkyl” refers to a straight, or branched chain saturatedhydrocarbon containing 1-12 carbon atoms, preferably 1-6 carbon atoms.Examples of a (C₁-C₆) alkyl group include, but are not limited to,methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

The term “alkynyl” refers to a straight, or branched chain unsaturatedhydrocarbon containing 2-12 carbon atoms. The “alkynyl” group containsat least one triple bond in the chain. Examples of alkynyl groupsinclude ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, orhexynyl.

The term “aromatic” means a planar ring having 4n+2 electrons in aconjugated system. As used herein, “conjugated system” means a system ofconnected p-orbitals with delocalized electrons, and the system mayinclude lone electron pairs.

The term “aryl” unless otherwise specifically defined refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic, or bicyclic groups such as phenyl, biphenyl, or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). Furthermore, when containing two fused rings thearyl groups herein defined may have one, or more saturated, or partiallyunsaturated ring fused with a fully unsaturated aromatic ring. Exemplaryring systems of these aryl groups include, but are not limited to,phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

The term “carrier” encompasses carriers, excipients, and diluents, andmeans a material, composition, or vehicle, such as a liquid, or solidfiller, diluent, excipient, solvent, or encapsulating material, involvedin carrying, or transporting a pharmaceutical agent from one organ, orportion of the body, to another organ, or portion of the body of asubject.

The term “cyano” means a substituent having a carbon atom joined to anitrogen atom by a triple bond, i.e., C≡N.

The term “cycloalkyl” means mono, or polycyclic saturated carbon ringscontaining 3-18 carbon atoms, preferably 3-10 carbon atoms. Examples ofcycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl,norborenyl, bicyclo[2.2.2]octanyl, and bicyclo[2.2.2]octenyl.

The term “disorder” means, and is used interchangeably with, the termsdisease, condition, or illness, unless otherwise indicated.

The term “haloalkoxy” refers to an alkoxy group, as defined herein,which is substituted with one, or more halogen. Examples of haloalkoxygroups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, and trichloromethoxy.

The term “haloalkyl” refers to an alkyl group, as defined herein, whichis substituted with one, or more halogen. Examples of haloalkyl groupsinclude, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, and trichloromethyl.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine, oriodine.

The term “heteroaryl” unless otherwise specifically defined means amonovalent monocyclic, or a polycyclic aromatic radical of 5 to 24 ringatoms, preferably 5 to 10 ring atoms, containing one, or more ringheteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4ring heteroatoms selected from N, O, or S, the remaining ring atomsbeing C. A polycyclic aromatic radical includes two, or more fusedrings, and may further include two, or more spiro-fused rings, e.g.,bicyclic, tricyclic, tetracyclic, and the like. Unless otherwisespecifically defined, “fused” means two rings sharing two ring atoms.Unless otherwise specifically defined, “spiro-fused” means two ringssharing one ring atom. Heteroaryl as herein defined also means abicyclic heteroaromatic group wherein the heteroatom is selected from N,O, S, P, or B, preferably N, O, or S. Heteroaryl as herein defined alsomeans a tricyclic heteroaromatic group containing one, or more ringheteroatoms selected from N, O, S, P, or B, preferably N, O, or S.Heteroaryl as herein defined also means a tetracyclic heteroaromaticgroup containing one, or more ring heteroatoms selected from N, O, S, P,or B, preferably N, O, or S. Examples of heteroaromatic groups include,but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl,pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl,indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl,thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene,triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl,imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl,thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl,benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl,dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl,benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, and3H-indolyl. Furthermore, when containing two, or more fused rings, theheteroaryl groups defined herein may have one, or more saturated, orpartially unsaturated ring fused with one, or more fully unsaturatedaromatic ring. In heteroaryl ring systems containing more than two fusedrings, a saturated, or partially unsaturated ring may further be fusedwith a saturated, or partially unsaturated ring described herein.Furthermore, when containing three, or more fused rings, the heteroarylgroups defined herein may have one, or more saturated, or partiallyunsaturated ring spiro-fused. Any saturated, or partially unsaturatedring described herein is optionally substituted with one, or more oxo.Exemplary ring systems of these heteroaryl groups include, for example,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran,chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl,oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl,7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl,1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl,7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl,pyrazolo[1,5-a]pyrimidin-7(4H)-onyl,3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl,benzo[c][1,2]oxaborol-1(3H)-olyl,6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-onyl,and6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-onyl.

The term “heterocyclyl”, “heterocycle”, or “heterocycloalkyl” meansmono, or polycyclic rings containing 3-24 atoms, preferably 3-10 atoms,which include carbon, and one, or more heteroatoms selected from N, O,S, P, or B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, andS, and wherein the rings are not aromatic. Examples of heterocyclylrings include, but are not limited to, oxetanyl, azetidinyl,tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl,and homotropanyl.

The term “isomers” refers to compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterised by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomers or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “modulate”, “modulation”, or “modulating” refers to abiological activity of a compound, or substrate that inhibits and/oractivates PI3K.

The term “patient”, or “subject” is a mammal, e.g., a human, mouse, rat,guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as amonkey, chimpanzee, baboon, or rhesus. Preferably, the mammal is human.

The term “therapeutically effective amount” when used in connection witha compound refers to the amount or dose of the compound which uponsingle or multiple dose administration to the patient, provides thedesired effect in the patient under diagnosis or treatment. An effectiveamount can be determined by one skilled in the art by the use of knowntechniques and by observing results obtained under analogouscircumstances. In determining the effective amount for a patient, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of patient; its size, age,and general health; the specific disease or disorder involved; thedegree of or involvement or the severity of the disease or disorder; theresponse of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances.

The term “treating” with regard to a subject, includes restraining,slowing, stopping, or reversing the progression or severity of anexisting symptom or disorder.

Compounds of the Present Invention

In one aspect, the present invention provides compounds of Formula (I),or pharmaceutically acceptable salts thereof:

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, R₇, and R₈, are as defined in theSummary for Formula (I).

In a further aspect, compounds of Formula (I) wherein R₈ is H haveFormula (II), or pharmaceutically acceptable salts thereof:

wherein R, R₁, R₂, R₃, R₄, R₅, R₆, and R₇, are as defined in the Summaryfor Formula (I).

In a compound of Formula (I), or (II), or pharmaceutically acceptablesalts thereof, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

wherein R₁₀ is independently —H, —CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,—OH, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₃-C₅ cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, or an optionally substituted heteroaryl selectedfrom pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole;wherein the optionally substituted C₁-C₆ alkyl is optionally substitutedwith a —CN, —OH, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅cycloalkyl, phenyl, heterocycle or heteroaryl is each optionallysubstituted with one to three substituents each independently selectedfrom halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently H orC₁-C₃ alkyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, halogen, —CN, C₁-C₆ alkyl, C₁-C₆haloalkyl, oxetane, or isoxazole. In yet a further compound of Formula(I), or (II), or pharmaceutically acceptable salts thereof, R₃ is —H,—CN, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In yet a further compound ofFormula (I), or (II), or pharmaceutically acceptable salts thereof, R₃is H, CN, or C₁-C₃ alkyl or C₁-C₃ haloalkyl (preferably R₃ is H, —CN, orC₁-C₃ alkyl); most preferably R₃ is H, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₄ is H or halogen, preferably R₄ is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl; preferably R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl;more preferably R₅ is H, halogen, methyl, or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₆ is H or halogen.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

wherein each R₁₀ is independently H, CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₅cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, or an optionally substituted heteroaryl selectedfrom pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole;wherein the optionally substituted C₁-C₆ alkyl is optionally substitutedwith a CN, —OH, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅cycloalkyl, phenyl, heterocycle or heteroaryl is each optionallysubstituted with one to three substituents each independently selectedfrom halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently H orC₁-C₃ alkyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₄ is H or halogen (preferably R₄ is H), andR₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

wherein each R₁₀ is independently H, CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₅cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, or an optionally substituted heteroaryl selectedfrom pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole;wherein the optionally substituted C₁-C₆ alkyl is optionally substitutedwith a CN, —OH, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅cycloalkyl, phenyl, heterocycle or heteroaryl is each optionallysubstituted with one to three substituents each independently selectedfrom halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently H orC₁-C₃ alkyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

wherein each R₁₀ is independently H, CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₅cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, or an optionally substituted heteroaryl selectedfrom pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole;wherein the optionally substituted C₁-C₆ alkyl is optionally substitutedwith a CN, —OH, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅cycloalkyl, phenyl, heterocycle or heteroaryl is each optionallysubstituted with one to three substituents each independently selectedfrom halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently H orC₁-C₃ alkyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₆ is H or halogen, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

wherein each R₁₀ is independently H, CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₅cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, or an optionally substituted heteroaryl selectedfrom pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole;wherein the optionally substituted C₁-C₆ alkyl is optionally substitutedwith a CN, —OH, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅cycloalkyl, phenyl, heterocycle or heteroaryl is each optionallysubstituted with one to three substituents each independently selectedfrom halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently H orC₁-C₃ alkyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl,and R₄ is H or halogen; more preferably R₃ is H, CN, or C₁-C₃ alkyl, andR₄ is H; most preferably R₃ is H, or methyl, and R₄ is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl,(preferably R₃ is H, CN, or C₁-C₃ alkyl), and R₅ is H, halogen, C₁-C₃alkyl or C₁-C₃ haloalkyl; more preferably R₃ is H, or methyl, and R₅ isH, halogen, methyl, or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl,(preferably R₃ is H, CN, or C₁-C₃ alkyl), and R₆ is H or halogen; morepreferably R₃ is H, or methyl, and R₆ is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₄ is —H or halogen (preferably R₄ is H), andR₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl; preferably R₅ is H,halogen, methyl, or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₄ is H or halogen (preferably R₄ is —H) andR₆ is H or halogen.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl, and R₆ is H or halogen; preferably R₅ is H, halogen, methyl,or trifluoromethyl, and R₆ is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl,(preferably R₃ is H, CN, or C₁-C₃ alkyl, more preferably R₃ is H, ormethyl), R₄ is —H or halogen (preferably R₄ is H), and R₂ is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with one to three R₁₀ substituents, or R₂ is a group of theformula:

Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl,(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₅ is H, halogen, C₁-C₆ alkyl,or C₁-C₆ haloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

more preferably R₃ is H, or methyl, and R₅ is H, halogen, methyl, ortrifluoromethyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl,(preferably R₃ is H, CN, or C₁-C₃ alkyl), and R₆ is H or halogen, and R₂is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

more preferably R₃ is H, or methyl, and R₆ is H. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₄ is H or halogen (preferably R₄ is H), R₅ isH, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

more preferably R₅ is H, halogen, methyl, or trifluoromethyl.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In a compound of Formula (I), or (II), or pharmaceutically acceptablesalts thereof, R₄ is H or halogen (preferably R₄ is H) and R₆ is H orhalogen, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

more preferably R₄ and R₆ are each H. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl, R₆ is H or halogen, and R₂ is a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, each optionally substituted with one tothree R₁₀ substituents, or R₂ is a group of the formula:

preferably R₅ is H, halogen, methyl, or trifluoromethyl, and R₆ is H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is H, CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₄ is H or halogen (preferablyR₄ is H), and R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl; morepreferably R₃ is H, or methyl, R₄ is H, and R₅ is H, halogen, methyl, ortrifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is H, CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₄ is H or halogen (preferablyR₄ is H) and R₆ is H or halogen; more preferably R₃ is H, or methyl, andR₄ and R₆ are each H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is H, CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₅ is H, halogen, C₁-C₃ alkylor C₁-C₃ haloalkyl, and R₆ is H or halogen; more preferably R₃ is H, ormethyl, R₅ is H, halogen, methyl, or trifluoromethyl, and R₆ is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl, R₄ is H or halogen (R₄ is H) and R₆ is H or halogen; morepreferably R₅ is H, halogen, methyl, or trifluoromethyl, and R₄ and R₆are each H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₄ is —H or halogen(preferably R₄ is H), R₅ is H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, orC₆ alkoxy, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

more preferably R₃ is H, or methyl, R₄ is H, and R₅ is H, halogen,methyl, or trifluoromethyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₄ is —H or halogen(preferably R₄ is —H), R₆ is H, and R₂ is a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, each optionally substituted with one tothree R₁₀ substituents, or R₂ is a group of the formula:

more preferably R₃ is H, or methyl, and R₄ and R₆ are each H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₅ is H, halogen, C₁-C₆ alkyl,or C₁-C₆ haloalkyl, R₆ is H or halogen, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

more preferably R₃ is H, or methyl, R₅ is H, halogen, methyl, ortrifluoromethyl, and R₆ is H. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl, R₄ is —H or halogen (preferably R₄ is H), R₆ is H or halogen,and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

more preferably R₅ is H, halogen, methyl, or trifluoromethyl, and R₄ andR₆ are each H. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is H, CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₄ is H or halogen (preferablyR₄ is H), R₆ is H or halogen, and R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl; preferably R₃ is H, or methyl, R₄ and R₆ are each H, and R₅is H, halogen, methyl, or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₄ is —H or halogen(preferably R₄ is H), R₆ is H or halogen, R₅ is H, halogen, C₁-C₃ alkylor C₁-C₃ haloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

more preferably R₃ is H, or methyl, R₄ and R₆ are each H, and R₅ is H,halogen, methyl, or trifluoromethyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is CN, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;preferably R₇ is CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl; more preferably R₇is CN, methyl or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₈ is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl, andR is H. In yet a further compound of Formula (I), or (II), orpharmaceutically acceptable salts thereof, R₇ is C₁-C₃ alkyl (preferablymethyl), and R is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₈ and R are each H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl, andR₈ is H. In yet a further compound of Formula (I), or (II), orpharmaceutically acceptable salts thereof, R₇ is C₁-C₃ alkyl (preferablymethyl), and R₈ is H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl, andR₈ and R are each H. In yet a further compound of Formula (I), or (II),or pharmaceutically acceptable salts thereof, R₇ is C₁-C₃ alkyl(preferably methyl), R₈ and R are H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₈is H, R is H, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is C₁-C₃ alkyl (preferably methyl), R₈ isH, R is H, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₇ is CN, C₁-C₃ alkyl or C₁-C₃haloalkyl, and R₈ and R are each H. In yet a further compound of Formula(I), or (II), or pharmaceutically acceptable salts thereof, R₃ is H, ormethyl, R₇ is C₁-C₃ alkyl (preferably methyl), and R₈ and R are each H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl, andR₄, R₈ and R are each H. In yet a further compound of Formula (I), or(II), or pharmaceutically acceptable salts thereof, R₇ is C₁-C₃ alkyl(preferably methyl), and R₄, R₈ and R are each H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl, R₇ is CN, methyl or trifluoromethyl, and R₈ and R are each H.In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, methyl, or trifluoromethyl,R₇ is methyl, and R₈ and R are each H.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl(preferably R₃ is H, CN, or C₁-C₃ alkyl), R₄ is —H or halogen(preferably R₄ is H), R₆ is H or halogen, R₅ is H, halogen, C₁-C₆ alkyl,or C₁-C₆ haloalkyl, R₇ is CN, methyl or trifluoromethyl, R₈ is H, R isH, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

more preferably R₃ is H, or methyl, R₄ and R₆ are each H, R₅ is H,halogen, methyl, or trifluoromethyl, R₇ is methyl, and R₈ and R are eachH. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl; preferably each R₉ is independently —H,halogen, methyl, trifluoromethyl, or cyclopropyl, more preferably eachR₉ is independently —H, halogen, methyl or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula

wherein each R₉ is independently —H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₃-C₅ cycloalkyl; preferably each R₉ isindependently —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy,or C₃-C₅ cycloalkyl; more preferably each R₉ is independently —H,halogen, methyl, trifluoromethyl, methoxy, or cyclopropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl. Preferably each R₉ is independently —H, halogen, methyl ortrifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or C₁-C₃ haloalkyl. Preferably R₉ is H, ortrifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, or C₁-C₃ haloalkyl. Preferably R₉ is —H, orhalogen. More preferably, R₉ is —H, or fluoro.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl. Preferably R₉ is independently —H, halogen, methyl,trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl. Preferably R₉ is —H, halogen, methyl, trifluoromethyl, orcyclopropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃haloalkyl, R₄ is —H, or halogen, R₆ is —H, or halogen, R₅ is —H,halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, and R₁ is a group of theformula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl. More preferably each R₉ is independently—H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably R₃ is—H, methyl, or trifluoromethyl, R₄ is —H, or halogen, R₆ is —H, orhalogen, R₅ is —H, halogen, methyl, or trifluoromethyl, and each R₉ isindependently —H, halogen, methyl, trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₇ is —CN, methyl or trifluoromethyl, R₈ and Rare each —H, and R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl; more preferably R₇ is methyl, R₈ and Rare each —H, and each R₉ is independently —H, halogen, methyl,trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃haloalkyl, R₄ is —H, or halogen, R₈ and R are each —H, R₅ is —H,halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₆ is —H, or halogen, R₇ is—CN, methyl or trifluoromethyl, and R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl; more preferably R₃ is —H, methyl, ortrifluoromethyl, R₄ is —H, or halogen, R₆ is —H, or halogen, R₈ and Rare each —H, R₅ is —H, halogen, methyl, or trifluoromethyl, R₇ ismethyl, and each R₉ is independently —H, halogen, methyl,trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃haloalkyl, R₄ is —H, or halogen, R₈ and R are each —H, R₅ is —H,halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₆ is —H, or halogen, R₇ is—CN, methyl or trifluoromethyl, and R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl; preferably R₃ is —H, methyl, or trifluoromethyl, R₄ is —H, orhalogen, R₆ is —H, or halogen, R₈ and R are each —H, R₅ is —H, halogen,methyl, or trifluoromethyl, R₇ is methyl, and each R₉ is independently—H, halogen, methyl or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is H, CN, or C₁-C₃ alkyl, R₄, R₆, R₈ and Rare each H, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₇ is CN,methyl or trifluoromethyl, and R₁ is a group of the formula:

wherein R₉ is H, halogen, or C₁-C₃ haloalkyl; preferably R₃ is H, ormethyl, R₄, R₆, R₈ and R are each H, R₅ is H, halogen, methyl, ortrifluoromethyl, R₇ is methyl, and R₉ is H, or trifluoromethyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is H, CN, or C₁-C₃ alkyl, R₄, R₆, R₈ and Rare each H, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₇ is CN,methyl or trifluoromethyl, and R₁ is a group of the formula:

wherein R₉ is —H, halogen, or C₁-C₃ haloalkyl; preferably R₃ is H, ormethyl, R₄, R₆, R₈ and R are each H, R₅ is H, halogen, methyl, ortrifluoromethyl, R₇ is methyl, and R₉ is —H, or halogen. Morepreferably, R₉ is —H, or fluoro.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃haloalkyl, R₄ is —H, or halogen, R₈ and R are each —H, R₅ is —H,halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₆ is —H, or halogen, R₇ is—CN, methyl or trifluoromethyl, and R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl; preferably R₃ is —H, methyl, or trifluoromethyl, R₄ is —H,or halogen, R₆ is —H, or halogen, R₈ and R are each —H, R₅ is —H,halogen, methyl, or trifluoromethyl, R₇ is methyl, and R₉ is —H,halogen, methyl, trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is H, CN, or C₁-C₃ alkyl, R₄, R₆, R₈ and Rare each H, R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₇ is CN,methyl or trifluoromethyl, and R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl; preferably R₃is H, or methyl, R₄, R₆, R₈ and R are each H, R₅ is H, halogen, methyl,or trifluoromethyl, R₇ is methyl, and R₉ is H, halogen, C₁-C₃ alkyl orC₁-C₃ haloalkyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃haloalkyl, R₄ is —H, or halogen, R₈ and R are each —H, R₅ is —H,halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₆ is —H, or halogen, R₇ is—CN, methyl or trifluoromethyl, and R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl; preferably R₃ is —H, methyl, or trifluoromethyl, R₄ is —H,or halogen, R₆ is —H, or halogen, R₈ and R are each —H, R₅ is —H,halogen, methyl, or trifluoromethyl, R₇ is methyl, and R₉ is —H,halogen, methyl, trifluoromethyl, or cycpropyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl, and R₂ is a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, each optionally substituted with one tothree R₁₀ substituents, or R₂ is a group of the formula:

wherein each R₁₀ is independently H, CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₅cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, or an optionally substituted heteroaryl selectedfrom pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole;wherein the optionally substituted C₁-C₆ alkyl is optionally substitutedwith a CN, —OH, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅cycloalkyl, phenyl, heterocycle or heteroaryl is each optionallysubstituted with one to three substituents each independently selectedfrom halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently H orC₁-C₃ alkyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, or C₁-C₃ alkyl or C₁-C₃haloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

preferably each R₉ is independently —H, halogen, methyl ortrifluoromethyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or C₁-C₃ haloalkyl, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

preferably R₉ is H, or trifluoromethyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or C₁-C₃ haloalkyl, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

preferably R₉ is H, or halogen. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

preferably R₉ is —H, halogen, methyl, trifluoromethyl, or cyclopropyl.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, and R₂ is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with one to three R₁₀ substituents, or R₂ is a group of theformula:

Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloallkyl,₄ is —H, or halogen, R₆is —H, or halogen, R₅ is —H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl,and R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl. Preferably R₃ is —H, methyl, ortrifluoromethyl, R₄ is —H, or halogen, R₆ is —H, or halogen, R₅ is —H,halogen, methyl, or trifluoromethyl, and each R₉ is independently —H,halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₇ is —CN, methyl or trifluoromethyl, R₈ and R are each —H, and R₁ is agroup of the formula:

wherein each R₉ is independently —H, halogen, methyl, C₁-C₃ haloalkyl,or cyclopropyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkymore preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, methyl or trifluoromethyl,R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

R₇ is C₁-C₃ alkyl (preferably methyl), and R₈ and R are each —H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkymore preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or trifluoromethyl, (preferably R₉ is H, ortrifluoromethyl), R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₇ is C₁-C₃ alkyl (preferably methyl), and R₈ and R are each H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or trifluoromethyl, (preferably R₉ is H, orhalogen), R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,each optionally substituted with one to three R₁₀ substituents, or R₂ isa group of the formula:

R₇ is C₁-C₃ alkyl (preferably methyl), and R₈ and R are each H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, methyl, trifluoromethyl, or cyclopropyl, R₂is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

R₇ is C₁-C₃ alkyl (preferably methyl), and R₈ and R are each —H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₂ is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with one to three R₁₀ substituents, or R₂ is a group of theformula:

R₇ is C₁-C₃ alkyl (preferably methyl), and R₈ and R are each H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,each optionally substituted with one to three R₁₀ substituents, or R₂ isa group of the formula:

R₇ is C₁-C₃ alkyl (preferably methyl), and R₈ and R are each —H.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is H, CN, or C₁-C₃ alkyl, R₄, R₆, R₈ and R are each H, R₅ is H,halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₇ is CN, methyl ortrifluoromethyl, and R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, methyl, C₁-C₃ haloalkyl,or cyclopropyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, methyl or trifluoromethyl,R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

R₃ is —H, methyl, or trifluoromethyl, R₄ is —H, or halogen, R₈ and R areeach —H, R₅ is —H, halogen, methyl or trifluoromethyl, R₆ is —H, orhalogen, and R₇ is C₁-C₃ alkyl (preferably methyl). Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or trifluoromethyl, (preferably R₉ is H, ortrifluoromethyl), R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is H, or methyl, R₄, R₆, R₈ and R are each H, R₅ is H, halogen,methyl, or trifluoromethyl, and R₇ is C₁-C₃ alkyl (preferably methyl).Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or trifluoromethyl, (preferably R₉ is H, orhalogen), R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,each optionally substituted with one to three R₁₀ substituents, or R₂ isa group of the formula:

R₃ is H, or methyl, R₄, R₆, R₈ and R are each H, R₅ is H, halogen,methyl, or trifluoromethyl, and R₇ is C₁-C₃ alkyl (preferably methyl).Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is independently —H, halogen, methyl, trifluoromethyl, orcyclopropyl, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is —H, methyl, or trifluoromethyl, R₄ is —H, or halogen, R₈ and R areeach —H, R₅ is —H, halogen, methyl or trifluoromethyl, R₆ is —H, orhalogen, and R₇ is C₁-C₃ alkyl (preferably methyl). Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₂ is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with one to three R₁₀ substituents, or R₂ is a group of theformula:

R₃ is H, or methyl, R₄, R₆, R₈ and R are each H, R₅ is H, halogen,methyl, or trifluoromethyl, and R₇ is C₁-C₃ alkyl (preferably methyl).Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), or (II), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, methyl, trifluoromethyl,or cyclopropyl, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is —H, methyl, or trifluoromethyl, R₄ is —H, or halogen, R₈ and R areeach —H, R₅ is —H, halogen, methyl or trifluoromethyl, R₆ is —H, orhalogen, and R₇ is C₁-C₃ alkyl (preferably methyl). Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In a further aspect, compounds of Formula (I) or (II) have Formula(III), or pharmaceutically acceptable salts thereof:

wherein R₁, R₂, R₃, R₅, R₆, and R₇ are as defined in the Summary forFormula (I) above.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, C₁-C₃ haloalkyl;preferably R₃ is H, CN, or C₁-C₃ alkyl; most preferably R₃ is H, ormethyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₅ is H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl; preferably R₅ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl;more preferably R₅ is H, halogen, methyl, or trifluoromethyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₆ is H or halogen; preferably R₆ is H.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₇ is CN, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;preferably R₇ is CN, C₁-C₃ alkyl or C₁-C₃ haloalkyl; more preferably R₇is CN, methyl or trifluoromethyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl; preferably each R₉ is independently —H,halogen, methyl, trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₃ -C₅ cycloalkyl. Preferably each R₉ isindependently —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl. More preferably each R₉ is independently —H, halogen,methyl, trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ independently —H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl. Preferably each R₉ is independently —H, halogen, methyl ortrifluoromethyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or C₁-C₃ haloalkyl. Preferably R₉ is H, ortrifluoromethyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl. Preferably each R₉ is independently —H, halogen, methyl ortrifluoromethyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl. Preferably R₉ is independently —H, halogen, methyl,trifluoromethyl, or cyclopropyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl. Preferably R₉ is —H, halogen, methyl, trifluoromethyl, orcyclopropyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl, and R₂ is a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, each optionally substituted with one tothree R₁₀ substituents, or R₂ is a group of the formula:

wherein each R₁₀ is independently H, CN, halogen, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, —SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁,an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₅cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, or an optionally substituted heteroaryl selectedfrom pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole;wherein the optionally substituted C₁-C₆ alkyl is optionally substitutedwith a CN, —OH, or C₁-C₃ alkoxy; the optionally substituted C₃-C₅cycloalkyl, phenyl, heterocycle or heteroaryl is each optionallysubstituted with one to three substituents each independently selectedfrom halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently H orC₁-C₃ alkyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₃-C₅ cycloalkyl, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

preferably each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl. Most preferably each R₉ is independently—H, halogen, methyl, trifluoromethyl, or cyclopropyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

preferably each R₉ is independently —H, halogen, methyl ortrifluoromethyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or C₁-C₃ haloalkyl, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

preferably R₉ is H, or trifluoromethyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or C₁-C₃ haloalkyl, and R₂ is a cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted withone to three R₁₀ substituents, or R₂ is a group of the formula:

preferably R₉ is H, or halogen. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

preferably R₉ is —H, halogen, methyl, trifluoromethyl, or cyclopropyl.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, and R₂ is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with one to three R₁₀ substituents, or R₂ is a group of theformula:

Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, or C₃-C₅cycloalkyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

preferably R₉ is —H, halogen, methyl, trifluoromethyl, or cyclopropyl.Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₃ is —H, —CN, C₁-C₃ alkyl, C₁-C₃ haloalkyl(preferably R₃ is —H, —CN, or C₁-C₃ alkyl), R₅ is —H, halogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl, R₆ is —H or halogen, R₇ is —CN, methyl ortrifluoromethyl, and R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

more preferably R₃ is —H, or methyl, R₅ is —H, halogen, methyl, ortrifluoromethyl, R₆ is —H, and R₇ is methyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl, R₅ is —H, halogen, C₁-C₃alkyl or C₁-C₃ haloalkyl, R₆ is —H or halogen, and R₁ is a group of theformula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl. Preferably R₃ is —H, methyl, ortrifluoromethyl, R₅ is —H, halogen, methyl, or trifluoromethyl, R₆ is —Hor halogen, and each R₉ is independently —H, halogen, methyl,trifluoromethyl, or cyclopropyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is —H, —CN, C₁-C₃ alkyl, or C₁-C₃ haloalkyl, R₅ is —H, halogen, C₁-C₃alkyl or C₁-C₃ haloalkyl, R₆ is —H or halogen, R₇ is —CN, methyl ortrifluoromethyl, and R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, C₁-C₃ alkyl, C₁-C₃haloalkyl, or C₃-C₅ cycloalkyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, methyl or trifluoromethyl,R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R₁₀ substituents, or R₂ is agroup of the formula:

R₃ is —H, methyl, or trifluoromethyl, R₅ is —H, halogen, methyl ortrifluoromethyl, R₆ is —H, or halogen, and R₇ is C₁-C₃ alkyl (preferablymethyl). Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or trifluoromethyl, (preferably R₉ is H, ortrifluoromethyl), R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is H, or methyl, R₅ is H, halogen, methyl, or trifluoromethyl, R₆ isH or halogen, and R₇ is methyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, or trifluoromethyl, (preferably R₉ is H, orhalogen), R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,each optionally substituted with one to three R₁₀ substituents, or R₂ isa group of the formula:

R₃ is H, or methyl, R₅ is H, halogen, methyl, or trifluoromethyl, R₆ isH or halogen, and R₇ is methyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, methyl, trifluoromethyl,or cyclopropyl, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is —H, methyl, or trifluoromethyl, R₅ is —H, halogen, methyl ortrifluoromethyl, R₆ is —H, or halogen, and R₇ is C₁-C₃ alkyl preferablymethyl). Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein R₉ is H, halogen, C₁-C₃ alkyl or C₁-C₃ haloalkyl, R₂ is acyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionallysubstituted with one to three R₁₀ substituents, or R₂ is a group of theformula:

R₃ is H, or methyl, R₅ is H, halogen, methyl, or trifluoromethyl, R₆ isH or halogen, and R₇ is methyl. Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (III), or pharmaceuticallyacceptable salts thereof, R₁ is a group of the formula:

wherein each R₉ is independently —H, halogen, methyl, trifluoromethyl,or cyclopropyl, R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each optionally substituted with one to three R₁₀substituents, or R₂ is a group of the formula:

R₃ is —H, methyl, or trifluoromethyl, R₅ is —H, halogen, methyl ortrifluoromethyl, R₆ is —H, or halogen, and R₇ is C₁-C₃ alkyl (preferablymethyl). Preferably, R₂ is

wherein R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl, preferably R₁₀ is independently —H, halogen, or C₁-C₃ alkyl,more preferably R₁₀ is independently —H, fluoro, or methyl.

In yet a further compound of Formula (I), the compound is selected from:

or a pharmaceutically acceptable salt of any of the foregoing; whereinthe bond at the * position is as represented,

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A further embodiment is a compound of Formula

or a pharmaceutically acceptable salt thereof. In yet a furtherembodiment, the bond at the * position is

In yet a further embodiment, the bond at the * position is

A pharmaceutically acceptable salt of a compound of the presentinvention is, for example, an acid-addition salt of a compound of theinvention, which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric, methane sulfonate or maleic acid. In addition, apharmaceutically acceptable salt of a compound of the present inventionwhich is sufficiently acidic is an alkali metal salt, for example asodium or potassium salt, an alkaline earth metal salt, for example acalcium or magnesium salt, an ammonium salt or a salt with an organicbase which affords a pharmaceutically acceptable cation, for example asalt with methylamine, dimethylamine, diethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine. Pharmaceuticallyacceptable salts, and common methodology for preparing them are wellknown in the art (see, e.g., P. Stahl, et al. Handbook of PharmaceuticalSalts: Properties, Selection, and Use, 2^(nd) Revised Edition(Wiley-VCH, 2011); S. M. Berge, et al., “Pharmaceutical Salts,” Journalof Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

Further representative “pharmaceutically acceptable salts” include,e.g., water-soluble, and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate,calcium, calcium edetate, camsylate, carbonate, chloride, citrate,clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate,fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate, pantothenate, phosphate/diphosphate,picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate,stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent invention can be synthesized by following the steps outlined inGeneral Scheme 1. Starting materials are either commercially availableor made by known procedures in the reported literature or as illustratedbelow.

Scheme 1 depicts the preparation of compounds of Formula (I), where R isH, R₇ is methyl, and R₈ is H. Acylation of substituted phenol (1) mayprovide ester (2). Ester (2) may undergo rearrangement under Lewis acidconditions to provide hydroxy aryl ketone (3). Basic addition of anester into aryl ketone (3) may provide the diketo compound (4).

Acidic cyclization can provide the chromen-4-one core (5). Phenylbromide (5) can be acylated via palladium catalysis to produce acylchromen-4-one (6). Aryl ketone (6) can be reduced to hydroxy compound(7) with a reagent such as sodium borohydride. Use of a halogenatingagent such as phosphorus tribromide can be used to convert hydroxycompound (7) to the halo compound (8).

Halo compound (8) can be used to alkylate an arylamine to give compoundsof Formula (I), followed by hydrolysis of ester present on R₁.

Pharmaceutical Compositions

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising a compound of Formula (I), (II), or (III) as anactive ingredient. In some embodiments, the present disclosure providesa pharmaceutical composition comprising a compound of Formula (I), (II),or (III), or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers or excipients.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of Formula (I), (II), or (III) can be formulated for oraladministration in forms such as tablets, capsules (each of whichincludes sustained release or timed release formulations), pills,powders, granules, elixirs, tinctures, suspensions, syrups andemulsions. The compounds of Formula (I), (II), or (III) can also beformulated for intravenous (bolus or in-fusion), intraperitoneal,topical, subcutaneous, intramuscular or transdermal (e.g., patch)administration, all using forms well known to those of ordinary skill inthe pharmaceutical arts.

The formulation of the present disclosure may be in the form of anaqueous solution comprising an aqueous vehicle. The aqueous vehiclecomponent may comprise water and at least one pharmaceuticallyacceptable excipient. Suitable acceptable excipients include thoseselected from the group consisting of a solubility enhancing agent,chelating agent, preservative, tonicity agent, viscosity/suspendingagent, buffer, and pH modifying agent, and a mixture thereof.

According to a further aspect of the disclosure there is provided apharmaceutical composition which comprises a compound any one of theFormulae disclosed herein, or a pharmaceutically acceptable salt,hydrate or solvate thereof, in association with a pharmaceuticallyacceptable diluent or carrier.

The compositions of the disclosure may be in a form suitable for oraluse (for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the disclosure may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more coloring, sweetening, flavoring and/or preservativeagents.

Methods of Use

In some aspects, the present disclosure provides a method of modulatingPI3K (e.g., PI3Kα) activity (e.g., in vitro or in vivo), comprisingcontacting a cell with a therapeutically effective amount of a compoundof Formula (I), (II), or (III), or a pharmaceutically acceptable saltthereof

In some aspects, the present disclosure provides a method of treating orpreventing a disease or disorder disclosed herein in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the present disclosure.

In some aspects, the present disclosure provides a method of treating adisease or disorder disclosed herein in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the present disclosure.

In some embodiments, the disease or disorder is associated with animplicated PI3K activity. In some embodiments, the disease or disorderis a disease or disorder in which PI3K activity is implicated.

In some embodiments, the disease or disorder is a cancer.

In some embodiments, the cancer is selected from acute lymphoblasticleukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma,aids-related cancers, aids-related lymphoma, anal cancer, astrocytoma,basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer,osteosarcoma, malignant fibrous histiocytoma, brain tumors, breastcancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer ofunknown primary, cardiac (heart) tumors, atypical teratoid/rhabdoidtumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma,chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenousleukemia (CIVIL), colorectal cancer, craniopharyngioma, cutaneous t-celllymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ(DCIS), embryonal tumors, medulloblastoma, endometrial cancer,ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma,extracranial germ cell tumor, extragonadal germ cell tumor, fallopiantube cancer, gallbladder cancer, gastric cancer, gastrointestinalcarcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germcell tumors, gestational trophoblastic disease, hairy cell leukemia,head and neck cancer, hepatocellular cancer, Langerhans cellhistiocytosis, Hodgkin lymphoma, islet cell tumors, pancreaticneuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer,leukemia, liver cancer, lung cancer, lymphoma, male breast cancer,intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma,metastatic cancer, metastatic squamous neck cancer, midline tractcarcinoma with nut gene changes, mouth cancer, multiple endocrineneoplasia syndromes, multiple myeloma/plasma cell neoplasms,myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferativeneoplasms, chronic myeloproliferative neoplasm, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip andoral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytomaof bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrinetumors (islet cell tumors), papillomatosis, paraganglioma, paranasalsinus and nasal cavity cancer, parathyroid cancer, penile cancer,pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cellneoplasm, multiple myeloma, pleuropulmonary blastoma, primary centralnervous system (CNS) lymphoma, primary peritoneal cancer, prostatecancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma,childhood vascular tumors, skin cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, squamous cell carcinoma of theskin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer,thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors,transitional cell cancer of the renal pelvis and ureter, urethralcancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer,and Wilms tumor.

In some embodiments, the cancer is Endometrial cancer, Breast cancer,Oesophageal squamous-cell cancer, Cervical squamous-cell carcinoma,Cervical adenocarcinoma, Colorectal adenocarcinoma, Bladder UrothelialCarcinoma, Glioblastoma, Ovarian cancer, Non-small-cell Lung cancer,Esophagogastric cancer, Nerve-sheath tumor, Head and neck squamous-cellcarcinoma, Melanoma, Esophagogastric adenocarcinoma, Soft-tissuesarcoma, Prostate cancer, Fibrolamellar carcinoma, Hepatocellularcarcinoma, Diffuse glioma, Colorectal cancer, Pancreatic cancer,Cholangiocarcinoma, B-cell lymphoma, Mesothelioma, Adrenocorticalcarcinoma, Renal non-clear-cell carcinoma, Renal clear-cell carcinoma,Germ-cell carcinoma, Thymic tumor, Pheochromocytoma, Miscellaneousneuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

In some embodiments, the cancer is a breast cancer, a prostate cancer,or a brain cancer.

In some embodiments, the cancer is a breast cancer. In some embodiments,the cancer is a prostate cancer. In some embodiments, the cancer is abrain cancer.

In some embodiments, the breast cancer is metastatic breast cancer. Insome embodiments, the breast cancer is ductal carcinoma in situ (DCIS).In some embodiments, the breast cancer is invasive ductal carcinoma. Insome embodiments, the breast cancer is triple negative breast cancer. Insome embodiments, the breast cancer is medullary carcinoma. In someembodiments, the breast cancer is tubular carcinoma. In someembodiments, the breast cancer is mucinous carcinoma. In someembodiments, the breast cancer is Paget disease of the breast or nipple.In some embodiments, the breast cancer is inflammatory breast cancer(IBC).

In some embodiments, the prostate cancer is an adenocarcinoma. In someembodiments, the prostate cancer is a small cell carcinoma. In someembodiments, the prostate cancer is a neuroendocrine tumor. In someembodiments, the prostate cancer is a transitional cell carcinoma. Insome embodiments, the prostate cancer is a sarcoma.

In some embodiments, the brain cancer is an acoustic neuroma. In someembodiments, the brain cancer is an astrocytoma. In some embodiments,the brain cancer is a brain metastasis. In some embodiments, the braincancer is choroid plexus carcinoma. In some embodiments, the braincancer is craniopharyngioma. In some embodiments, the brain cancer is anembryonal tumor. In some embodiments, the brain cancer is an ependymoma.In some embodiments, the brain cancer is a glioblastoma. In someembodiments, the brain cancer is a glioma. In some embodiments, thebrain cancer is a medulloblastoma. In some embodiments, the brain canceris a meningioma. In some embodiments, the brain cancer is anoligodendroglioma. In some embodiments, the brain cancer is a pediatricbrain tumor. In some embodiments, the brain cancer is a pineoblastoma.In some embodiments, the brain cancer is a pituitary tumor.

In some embodiments, the disease or disorder associated with PI3Kincludes, but is not limited to, CLOVES syndrome (congenial lipomatousovergrowth, vascular malformations, epidermal naevi, scoliosis/skeletaland spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), breastcancer, brain cancer, prostate cancer, endometrial cancer, gastriccancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer,ovarian cancer, skin cancer, or head and neck cancer.

In some embodiments, the diseases or disorder associated with PI3K isCLOVES syndrome (congenital lipomatous overgrowth, vascularmalformations, epidermal naevi, scoliosis/skeletal and spinal syndrome).

In some embodiments, the disease or disorder associated with PI3K isPIK3CA-related overgrowth syndrome (PROS).

In some embodiments, the disease or disorder associated with PI3K isbreast cancer, brain cancer, prostate cancer, endometrial cancer,gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lungcancer, ovarian cancer, skin cancer, or head and neck cancer.

In some embodiments, the disease or disorder associated with PI3K isbreast cancer, brain cancer, prostate cancer, endometrial cancer,gastric cancer, colorectal cancer, lung cancer, ovarian cancer, skincancer, or head and neck cancer.

In some embodiments, the disease or disorder associated with PI3K isleukemia, lymphoma, or sarcoma.

In some embodiments, the cancer is endometrial cancer, head and neckcancer, or a sarcoma.

In some embodiments, the cancer is endometrial cancer. In someembodiments the cancer is head and neck cancer. In some embodiments, thecancer is a sarcoma.

In some embodiments, the sarcoma is soft tissue sarcoma, osteosarcoma,chondrosarcoma, Ewing sarcoma, hemangioendothelioma, angiosarcoma,fibrosarcoma, myofibrosarcoma, chordoma, adamantinoma, liposarcoma,leiomyosarcoma, malignant peripheral nerve sheath tumor,rhabdomyosarcoma, synovial sarcoma, or malignant solitary fibrous tumor.

In some embodiments, the sarcoma is soft tissue sarcoma. In someembodiments the soft tissue sarcoma is liposarcoma, atypical lipomatoustumor, dermatofibrosarcoma protuberans, malignant solitary fibroustumor, inflammatory myofibroblastic tumor, low-grade myofibroblasticsarcoma, fibrosarcoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma,giant cell tumor of soft tissues, leiomyosarcoma, malignant glomustumor, rhabdomyosarcoma, hemangioendothelioma, angiosarcoma of softtissue, extraskeletal osteosarcoma, gastrointestinal stromal tumor,malignant gastrointestinal stromal tumor (GIST), malignant peripheralnerve sheath tumor, malignant Triton tumor, malignant granular celltumor, malignant ossifying fibromyxoid tumor, stromal sarcoma,myoepithelial carcinoma, malignant phosphaturic mesenchymal tumor,synovial sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clearcell sarcoma of soft tissue, extraskeletal myxoid chondrosarcoma,extraskeletal Ewing sarcoma, desmoplastic small round cell tumor,extrarenal rhabdoid tumor, perivascular epithelioid cell tumor, intimalsarcoma, undifferentiated spindle cell sarcoma, undifferentiatedpleomorphic sarcoma, undifferentiated round cell sarcoma,undifferentiated epithelioid sarcoma, or undifferentiated sarcoma, nototherwise specified.

In some aspects, the present disclosure provides a method of treating orpreventing a cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of the presentdisclosure.

In some aspects, the present disclosure provides a method of treating acancer in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I),(II), or (III), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of the present disclosure.

In some aspects, the present disclosure provides a method of treating orpreventing a breast cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of the presentdisclosure.

In some aspects, the present disclosure provides a method of treating abreast cancer in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of the present disclosure.

In some aspects, the present disclosure provides a method of treating orpreventing a prostate cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of the presentdisclosure.

In some aspects, the present disclosure provides a method of treating aprostate cancer in a subject in need thereof, comprising administeringto the subject a therapeutically effective amount of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the present disclosure.

In some aspects, the present disclosure provides a method of treating orpreventing a brain cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition of the presentdisclosure.

In some aspects, the present disclosure provides a method of treating abrain cancer in a subject in need thereof, comprising administering tothe subject a therapeutically effective amount of a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of the present disclosure.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in therapy.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in modulating PI3K (e.g., PI3Kα) activity (e.g., in vitro or invivo).

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating or preventing a disease or disorder disclosed herein.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating a disease or disorder disclosed herein.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating or preventing a cancer.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating a cancer.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating or preventing a breast cancer.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating a breast cancer.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating or preventing a prostate cancer.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating a prostate cancer.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating or preventing a brain cancer.

In some aspects, the present disclosure provides a compound of Formula(I), (II), or (III), or a pharmaceutically acceptable salt thereof foruse in treating a brain cancer.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for modulating PI3K (e.g.,PI3Kα) activity (e.g., in vitro or in vivo).

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating or preventing adisease or disorder disclosed herein.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating a disease ordisorder disclosed herein.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating or preventing acancer in a subject in need thereof.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating a cancer in asubject in need thereof.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating or preventing abreast cancer in a subject in need thereof.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating a breast cancerin a subject in need thereof.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating or preventing aprostate cancer in a subject in need thereof.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating a prostatecancer in a subject in need thereof.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating or preventing abrain cancer in a subject in need thereof.

In some aspects, the present disclosure provides use of a compound ofFormula (I), (II), or (III), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating a brain cancerin a subject in need thereof.

The present disclosure provides compounds that function as modulators ofPI3K activity. The present disclosure therefore provides a method ofmodulating PI3K activity in vitro or in vivo, said method comprisingcontacting a cell with a therapeutically effective amount of a compound,or a pharmaceutically acceptable salt thereof, as defined herein.

In some embodiments, PI3K modulation is inhibition of PI3K.

In some embodiments, the PI3K inhibitor is a PI3Kα inhibitor. In someembodiments, the PI3K inhibitor is a PI3Kα H1047R mutant inhibitor.

Effectiveness of compounds of the disclosure can be determined byindustry-accepted assays/disease models according to standard practicesof elucidating the same as described in the art and are found in thecurrent general knowledge.

The present disclosure also provides a method of treating a disease ordisorder in which PI3K activity is implicated in a patient in need ofsuch treatment, said method comprising administering to said patient atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition as definedherein.

Routes of Administration

The compounds of Formula (I), (II), or (III), or pharmaceuticalcompositions comprising these compounds may be administered to a subjectby any convenient route of administration, whethersystemically/peripherally or topically (i.e., at the site of desiredaction).

Routes of administration include, but are not limited to, oral (e.g. byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intra-arterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

EXAMPLES

Exemplary compounds of Formula (I), (II), and (III) are synthesized andtested in the examples. It is understood that compounds of Formula (I),(II), and (III) may be converted to the corresponding pharmaceuticallyacceptable salts of the compounds using routine techniques in the art(e.g., by saponification of an ester to the carboxylic acid salt, or byhydrolyzing an amide to form a corresponding carboxylic acid and thenconverting the carboxylic acid to a carboxylic acid salt).

Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300MHz as stated and at 300.3 K unless otherwise stated; the chemicalshifts (δ) are reported in parts per million (ppm). Spectra wererecorded using a Bruker or Varian instrument with 8, 16 or 32 scans.

LC-MS chromatograms and spectra were recorded using an Agilent 1200 orShimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as aLuna-C18 2.0×30 mm or Xbridge Shield RPC18 2.1×50 mm. Injection volumeswere 0. -8.0 μl and the flow rates were typically 0.8 or 1.2 ml/min.Detection methods were diode array (DAD) or evaporative light scattering(ELSD) as well as positive ion electrospray ionization. MS range was100-1000 Da. Solvents were gradients of water and acetonitrile bothcontaining a modifier (typically 0.01-0.04%) such as trifluoroaceticacid or ammonium carbonate.

Abbreviations

AcOH/HOAc Acetic Acid

ADP Adenosine diphosphate

ATP Adenosine triphosphate

CDCl₃ Chloroform-d

DCM Dichloromethane

DIEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

DMSO-d₆ Hexadeuterodimethylsulfoxide

eq. equivalents

EtI Ethyl iodide

EtOAc ethyl acetate

h hour(s)

HEPES 4- (2-hydroxyethyl)-1-piperazineethanesulfonic acid

¹H NMR Proton nuclear magnetic resonance spectroscopy

LC-MS Liquid chromatography-mass spectrometry

MeOH Methanol

min minute(s)

NaHMDS Sodium bis(trimethylsilyl)amide

PIP2 Phosphatidylinositol 4,5-bisphosphate

PPh₃ triphenylphosphine

ppm parts per million

rt room temperature

TFA trifluoroacetic acid

THF Tetrahydrofuran

Ti(i-PrO)₄ Titanium(IV) isopropoxide

Intermediate 1: (2-Bromo-4-methyl-phenyl) propanoate

A mixture of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) and pyridine(6.34 g, 80.2 mmol) in DCM (100 mL) was added propanoyl chloride (5.44g, 58.8 mmol) at 0° C., and stirred at 25° C. for 16 h. Then the mixturewas diluted with water (100 mL), adjusted to pH=5 with HCl (2 M) andextracted with DCM (100 mL×2). The combined extract was washed withbrine (150 mL×2), dried over anhydrous Na₂SO₄, filtered, andconcentrated to give the product as an oil (13 g, crude). ¹H NMR (400MHz, DMSO-d6) δ ppm 1.17 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.62 (q, J=7.6Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.50-7.55 (m, 1H).

Intermediate 2: 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)propan-1-one

A mixture of (2-bromo-4-methyl-phenyl) propanoate (12.5 g, 51.4 mmol)and AlCl₃ (24.0 g, 180 mmol) was stirred at 140° C. for 1 h. When cooledto rt, the mixture was quenched with water (80 mL) dropwise and stirredfor 30 min. Then the mixture was extracted with EtOAc (100 mL×3). Thecombined extract was washed with brine (200 mL×2), dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and triturated withpetroleum ether (20 mL) to give the product as a solid (9.82 g, 79%). ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.15(q, J=7.2 Hz, 2H), 7.66-7.73 (m, 1H), 7.77-7.83 (m, 1H), 12.66 (s, 1H).

Intermediate 3: 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)ethanone

A mixture of 1-(2-hydroxy-5-methyl-phenyl)ethanone in acetic acid (80mL) was treated with sodium acetate (6.56 g, 79.91 mmol). The reactionwas cooled to 0° C. and treated dropwise with bromine (12.77 g, 79.91mmol). After addition was completed, the reaction was stirred at rt for20 h. The reaction was poured into 400 mL of ice water and thesuspension filtered to give the product (13 g, 85%) as a yellow solid.¹H NMR (400 MHz, CDCl₃) δ ppm 2.33 (s, 3H), 2.65 (s, 3H), 7.50 (s, 1H),7.60 (s, 1H), 12.64 (s, 1H).

Intermediate 4: Methyl 1-phenylcyclopropanecarboxylate

1-Phenylcyclopropanecarboxylic acid (5.3 g, 33 mmol) was dissolved in 50mL of methanol and treated in portions with acetyl chloride. Afteraddition was complete, allowed the reaction to stir at room temperaturefor 18 h. Concentrated the reaction and diluted the residue with waterand ethyl acetate. Added saturated aqueous sodium bicarbonate toneutralize the residue and separated the layers. Re-extracted theaqueous layer three times with 100 mL of ethyl acetate. The organicswere combined, dried over MgSO₄, filtered, and concentrated to give theproduct (4.5 g, 66%) as a clear liquid. MS ES+ m/z 177 [M+H]⁺.

Intermediate 5: Methyl indane-2-carboxylate

A mixture of indane-2-carboxylic acid (3 g, 18.50 mmol) in 30 mL ofmethanol was treated with sulfuric acid (0.18 g, 1.85 mmol) and stirredat 60° C. for 12 hr. The reaction was concentrated, the residuedissolved in 100 mL of dichloromethane, washed with saturated aqueoussodium bicarbonate, collected, dried over Na₂SO₄, filtered, andconcentrated to give the product (3.15 g, 17.88 mmol) which was usedwithout purification. MS ES+ m/z 177 [M+H]⁺.

Intermediate 45: Indane-2-carbonyl chloride

A mixture of indane-2-carboxylic acid (6.0 g, 37.0 mmol) in 60 mL ofdichloromethane was treated with DMF (0.27 g, 0.28 mL, 3.70 mmol) andcooled to 0° C. When cold, the reaction was treated with oxalyl chloride(7.04 g, 55.49 mmol) and then stirred at 25° C. for 2 hr. The resultingyellow solution was concentrated and taken on to the next synthetic stepwithout purification.

Intermediate 6: (2-Bromo-4-methyl-6-propanoyl-phenyl)4,4-difluorocyclohexanecarboxylate

1-(3-Bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (5.0 g, 20.57 mmol)was dissolved in 50 mL of dichloromethane and cooled to 0° C. Thesolution was treated with triethylamine (10.41 g, 102.84 mmol),4-dimethylaminopyridine (3.77 g, 30.85 mmol), anddifluorocyclohexanecarbonyl chloride (7.50 g, 41.02 mmol) and thenallowed to stir at 15° C. for 16 h under nitrogen. The yellow suspensionwas diluted with 50 mL of water, the pH adjusted to 3 with 1M aqueoushydrogen chloride, and extracted with 50 mL of dichloromethane. Theorganic layer was washed with 50 mL of saturated aqueous sodiumbicarbonate, brine, collected, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatographyeluted with 0% to 10% ethyl acetate in petroleum ether to give thecompound (7.85 g, 98%) as a yellow oil.

The following compounds in Table 1 were made in a similar way asdescribed for Intermediate 6.

TABLE 1 MS ES+ Int # Chemical Name Structure m/z 46 (2-Bromo-4-methyl-6-propanoyl-phenyl)indane- 2-carboxylate

Material used without purification

Intermediate 7:1-(3-Bromo-2-hydroxy-5-methyl-phenyl)-3-cyclohexyl-propane-1,3-dione

A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (1 g, 4.37mmol) in 10 mL of THF was cooled to 0° C. in an ice bath. When cold,treated the reaction with lithium diisopropylamide (2M, 1.40 g, 13.10mmol) and allowed to stir at 0° C. After 30 min, the reaction wastreated with a solution of methyl cyclohexanecarboxylate (1.24 g, 8.73mmol) in 5 mL of THF. After addition was complete, the reaction wasstirred at rt for 16 h. The resulting yellow solution was diluted withsaturated aqueous ammonium chloride (20 mL) and extracted twice with 20mL of ethyl acetate. The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified bysilica gel chromatography eluted with 0% to 5% ethyl acetate inpetroleum ether to give the product (0.70 g, 48%) as a yellow oil. MSES+ m/z 339 [M+H]⁺.

Intermediate 8:1-(3-Bromo-2-hydroxy-5-methyl-phenyl)-3-(4,4-dimethylcyclohexyl)propane-1,3-dione

A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)ethanone (0.50 g,2.18 mmol) and methyl 4,4-dimethylcyclohexanecarboxylate (0.45 g, 2.62mmol) in 20 mL of THF was cooled to 0° C. and treated in portions withsodium hydride (0.26 g, 60%, 6.55 mmol). After addition was complete,allowed the reaction to stir at rt for 32 h. Carefully quenched thereaction with 20 mL of water and extracted three times with 20 mL ofdichloromethane. The combined organics were washed with brine,collected, dried over Na₂SO₄, filtered, and concentrated. The residuewas purified by silica gel chromatography eluted with 0% to 17% ethylacetate in petroleum ether to give the product (0.50 g, 62%) as a yellowsolid. MS ES+ m/z 369 [M+H]⁺.

The following compounds in Table 2 were made in a similar way asdescribed for Intermediate 8.

TABLE 2 MS ES+ Int # Chemical Name Structure m/z  91-(3-Bromo-2-hydroxy- phenyl)-3-cyclohexyl- propane-1,3-dione

327 [M + H]⁺ 10 1-(3-Bromo-2-hydroxy-5- methyl-phenyl)-3-(1-phenylcyclopropyl)propane- 1,3-dione

Product does not ionize well. 11 1-(3-Bromo-2-hydroxy-5-methyl-phenyl)-3-(4,4- difluorocyclohexyl)propane- 1,3-dione

375 [M + H]⁺ 12 1-(3-Bromo-2-hydroxy-5- methyl-phenyl)-3-indan-2-yl-propane-1,3-dione

375 [M + H]⁺ 47 1-(3-Bromo-2-hydroxy-5- methyl-phenyl)-3-indan-2-yl-2-methyl-propane-1,3- dione

Material used without purification

Intermediate 13:8-Bromo-2-(4,4-difluorocyclohexyl)-3,6-dimethyl-chromen-4-one

(2-Bromo-4-methyl-6-propanoyl-phenyl) 4,4-difluorocyclohexanecarboxylate(4.0 g, 10.28 mmol) was dissolved in 40 mL of 2-methyltetrahydrofuranand cooled to 0° C. When cold, the reaction was treated with sodiumhydride (1.23 g, 60% wt, 30.83 mmol) and then removed from the coolingbath and stirred at 80° C. for 1 h. The reaction was quenched with 80 mLof saturated aqueous ammonium chloride and extracted three times with 80mL of ethyl acetate. The organic layers were combined, washed with 100mL of brine, collected, dried over Na₂SO₄, filtered, and concentrated togive the product (4 g crude) without purification. MS ES+ m/z 373[M+H]⁺.

Intermediate 14: 8-Bromo-2-cyclohexyl-6-methyl-chromen-4-one

A mixture of1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-cyclohexyl-propane-1,3-dione(0.50 g, 1.47 mmol) in acetic acid (5 mL) was treated with sulfuric acid(1 mL) and stirred at 100° C. for 1 h. The reaction was cooled to rt,poured into 20 mL of ice water, and extracted 3 times with 20 mL ofethyl acetate. The combined organics were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel chromatography eluted with 0% to 5% ethyl acetate in petroleum etherto give the product (0.24 g, 51%) as a light yellow solid which wastaken on to the next synthetic step without spectral analysis.

The following compounds in Table 3 were made in a similar way asdescribed for

Intermediate 14.

TABLE 3 MS ES+ Int # Chemical Name Structure m/z 15 8-Bromo-2-(4,4-dimethylcyclohexyl)-6- methyl-chromen-4-one

349 [M + H]⁺ 16 8-Bromo-2-cyclohexyl- chromen-4-one

307 [M + H]⁺ 17 8-Bromo-6-methyl-2-(1- phenylcyclopropyl)chromen- 4-one

355/357 [M + H]⁺ 18 8-Bromo-2-(4,4- difluorocyclohexyl)-6-methyl-chromen-4-one

359 [M + H]⁺ 19 8-Bromo-2-indan-2-yl-6- methyl-chromen-4-one

355 [M + H]⁺ 48 8-Bromo-2-indan-2-yl-3,6- dimethyl-chromen-4-one

369/371 [M + H]⁺

Intermediate 20: 8-Acetyl-2-cyclohexyl-6-methyl-chromen-4-one

A mixture of 8-bromo-2-cyclohexyl-6-methyl-chromen-4-one (0.34 mg, 1.06mmol) in 1,4-dioxane (8 mL) was treated withtributyl(1-ethoxyvinyl)stannane (1.14 g, 3.16 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.074 g, 0.011 mmol)under a nitrogen atmosphere and the reaction stirred at 95° C. for 16 h.The resulting black suspension was treated with 4 mL of aqueous hydrogenchloride (2M) and stirred at 25° C. for 1 h. The reaction was thendiluted with 20 mL of saturated aqueous potassium fluoride and 20 mL ofethyl acetate, filtered, and the solids washed with 20 mL of ethylacetate. The layers of the filtrate were separated and the aqueous layerre-extracted with 20 mL of ethyl acetate. The combined organics werewashed with saturated aqueous sodium bicarbonate (30 mL), brine (30 mL),collected, dried over Na₂SO₄, filtered, and concentrated. The residuewas purified by silica gel chromatography eluted with 0% to 25% ethylacetate in petroleum ether to give the product (0.24 g, 80%) as a whitesolid. MS ES+ m/z 285 [M+H]⁺.

The following compounds in Table 4 were made in a similar way asdescribed for Intermediate 20.

TABLE 4 MS ES+ Int # Chemical Name Structure m/z 21 8-Acetyl-2-(4,4-dimethylcyclohexyl)-6- methyl-chromen-4-one

313 [M + H]⁺ 22 8-Acetyl-2-cyclohexyl- chromen-4-one

271 [M + H]⁺ 23 8-Acetyl-6-methyl-2-(1- phenylcyclopropyl)chromen- 4-one

319 [M + H]⁺ 24 8-Acetyl-2-(4,4- difluorocyclohexyl)-6-methyl-chromen-4-one

321 [M + H]⁺ 25 8-Acetyl-2-(4,4- difluorocyclohexyl)-3,6-dimethyl-chromen-4-one

335 [M + H]⁺ 26 8-Acetyl-2-indan-2-yl-6- methyl-chromen-4-one

319 [M + H]+ 49 8-Acetyl-2-indan-2-yl-3,6- dimethyl-chromen-4-one

333 [M + H]⁺

Intermediate 27: 2-Cyclohexyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one

A solution of 8-acetyl-2-cyclohexyl-6-methyl-chromen-4-one (0.24 g, 0.84mmol) in dichloromethane (4 mL) and methanol (2 mL) was treated withsodium borohydride (0.035 g, 0.93 mmol) and the reaction allowed to stirat rt for 1 h. The reaction was quenched with 15 mL of water and thenextracted twice with 20 mL of dichloromethane. The combined organicswere washed with 30 mL of brine, collected, dried over Na₂SO₄, filtered,and concentrated to give the product (0.24 g, 99%) as a white solid. MSES+ m/z 287 [M+H]⁺.

The following compounds in Table 5 were made in a similar way asdescribed for Intermediate 27.

TABLE 5 MS ES+ Int # Chemical Name Structure m/z 282-(4,4-Dimethylcyclohexyl)-8- (1-hydroxyethyl)-6-methyl- chromen-4-one

315 [M + H]⁺ 29 2-Cyclohexyl-8-(1- hydroxyethyl)chromen-4-one

273 [M + H]⁺ 30 8-(1-Hydroxyethyl)-6-methyl-2-(1-phenylcyclopropyl)chromen- 4-one

321 [M + H]⁺ 31 2-(4,4-Difluorocyclohexyl)-8- (1-hydroxyethyl)-6-methyl-chromen-4-one

323 [M + H]⁺ 32 2-(4,4-Difluorocyclohexyl)-8-(1-hydroxyethyl)-3,6-dimethyl- chromen-4-one

337 [M + H]⁺ 33 8-(1-Hydroxyethyl)-2-indan-2- yl-6-methyl-chromen-4-one

321 [M + H]⁺ 50 8-(1-Hydroxyethyl)-2-indan-2-yl-3,6-dimethyl-chromen-4-one

335 [M + H]⁺

Intermediate 34: 8-(1-Bromoethyl)-2-cyclohexyl-6-methyl-chromen-4-one

A mixture of 2-cyclohexyl-8-(1-hydroxyethyl)-6-methyl-chromen-4-one(0.12 g, 0.42 mmol) in 5 mL of dichloromethane was cooled to 0° C. andtreated dropwise with phosphorus tribromide (0.34 g, 1.26 mmol). Afteraddition was complete, allowed the reaction to stir at rt for 16 h. Thereaction was cooled to 0° C., treated with 2 mL of water, and the pHadjusted to 8 with saturated aqueous sodium bicarbonate. The mixture wasextracted twice with 15 mL of dichloromethane. The combined organicswere washed with 20 mL of brine, collected, dried over Na₂SO₄, filtered,and concentrated to give the product 0.13 g, 90%) as a green solid. MSES+ m/z 351 [M+H]⁺.

The following compounds in Table 6 were made in a similar way asdescribed for Intermediate 34.

TABLE 6 MS ES+ Int # Chemical Name Structure m/z 358-(1-Bromoethyl)-2-(4,4- dimethylcyclohexyl)-6-methyl- chromen-4-one

377 [M + H]⁺ 36 8-(1-Bromoethyl)-2- cyclohexyl-chromen-4-one

337 [M + H]⁺ 37 8-(1-Bromoethyl)-6-methyl-2- (1-phenylcyclopropyl)chromen-4-one

383/385 [M + H]⁺ 38 8-(1-Bromoethyl)-2-(4,4-difluorocyclohexyl)-6-methyl- chromen-4-one

385 [M + H]⁺ 39 8-(1-Bromoethyl)-2-(4,4- difluorocyclohexyl)-3,6-dimethyl-chromen-4-one

399 [M + H]⁺ 40 8-(1-Bromoethyl)-2-indan-2- yl-6-methyl-chromen-4-one

385 [M + H]⁺ 51 8-(1-Bromoethyl)-2-indan-2- yl-3,6-dimethyl-chromen-4-one

397/399 [M + H]⁺

Intermediate 41: Methyl2-[1-(2-cyclohexyl-4-oxo-chromen-8-yl)ethylamino]benzoate

A mixture of 8-(1-bromoethyl)-2-cyclohexyl-chromen-4-one (0.10 g, 0.30mmol) and methyl 2-aminobenzoate (0.09 g, 0.60 mmol) in 2 mL of DMF wasstirred at 80° C. for 16 h. Combined with a second reaction of the sameamounts and concentrated. The residue was purified by silica gelchromatography eluted with 0% to 22% ethyl acetate in petroleum ether togive the product (0.25 g, 82%) as a yellow oil. MS ES+ m/z 406 [M+H]⁺.

Intermediate 42: tert-Butyl2-[1-[2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate

8-(1-Bromoethyl)-2-(4,4-difluorocyclohexyl)-6-methyl-chromen-4-one (0.10g, 0.26 mmol) was dissolved in 3 mL of DMF and treated with tert-butyl2-aminobenzoate (0.075 g, 0.39 mmol) and stirred at 80° C. for 16 h. Themixture was diluted with 10 mL of ice water and filtered to give a graysolid. Dissolved the solid in ethyl acetate, dried over Na₂SO₄,filtered, and concentrated to give the product (0.10 g, 77%) as a graysolid. MS ES+ m/z 498 [M+H]⁺.

The following compounds in Table 7 were made in a similar way asdescribed for Intermediate 42.

TABLE 7 MS ES+ Int # Chemical Name Structure m/z 43 tert-Butyl2-[1-[2-(4,4- difluorocyclohexyl)-3,6- dimethyl-4-oxo-chromen-8-yl]ethylamino]benzoate

512 [M + H]⁺ 44 tert-Butyl 2-[1-(2-indan-2-yl-6- methyl-4-oxo-chromen-8-yl)ethylamino]benzoate

496 [M + H]⁺ 52 tert-Butyl 2-[1-(2-indan-2-yl-3,6-dimethyl-4-oxo-chromen-8- yl)ethylamino]benzoate

510 [M + H]⁺

Example 1: 2-[1-(2-Cyclohexyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid

A mixture of methyl2-[1-(2-cyclohexyl-4-oxo-chromen-8-yl)ethylamino]benzoate (0.20 g, 0.48mmol) in 3 mL of methanol and 0.5 mL of water was treated with sodiumhydroxide (0.08 g, 1.93 mmol) and stirred at 45° C. for 16 h. Thereaction was concentrated and purified by preparative HPLC usingacetonitrile and water (with 0.05% ammonia hydroxide) to give theproduct (0.13 g, 69%) as a white solid. MS ES+ m/z 392 [M+H]⁺.

Example 2:2-[1-[2-(4,4-Difluorocyclohexyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoicacid

tert-Butyl2-[1-[2-(4,4-difluorocyclohexyl)-6-methyl-4-oxo-chromen-8-yl]ethylamino]benzoate(0.10 g, 0.20 mmol) was dissolved in 10 mL of dichloromethane andtreated with trifluoroacetic acid (3.08 g, 27.01 mmol) and stirred at20° C. for 16 h. The reaction was concentrated and the residue purifiedby reverse phase chromatography (C18-6; 30×100 mm; 5 um) eluted with 52%to 82% acetonitrile in water (with added trifluoroacetic acid) to givethe product (0.06 g, 66%) as a white solid. MS ES⁺m/z 442 [M+H]⁺.

The following compounds in Table 8 were made in a similar way asdescribed for Example 2.

TABLE 8 Example MS ES+ # Chemical Name Structure m/z  3 2-[1-[2-(4,4-Difluorocyclohexyl)-3,6- dimethyl-4-oxo-chromen-8- yl]ethylamino]benzoicacid

 4 2-[1-(2-Indan-2-yl-6-methyl- 4-oxo-chromen-8- yl)ethylamino]benzoicacid

440 [M + H]⁺ 20 2-[1-(2-Indan-2-yl-3,6- dimethyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid

454 [M + H]⁺

Example 5:2-[1-(2-Cyclohexyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid

A mixture of 8-(1-bromoethyl)-2-cyclohexyl-6-methyl-chromen-4-one (0.12g 0.34 mmol) and 2-aminobenzoic acid (0.094 g, 0.69 mmol) in 1 mL of DMFwas stirred at 80° C. for 14 h. The resulting brown suspension wasdiluted with 1 mL of DMF and purified by preparative HPLC to give theproduct (0.06 g, 43%) as a white solid. MS ES+ m/z 406 [M+H]⁺.

The following compounds in Table 9 were made in a similar way asdescribed for Example 5.

TABLE 9 Example MS ES+ # Chemical Name Structure m/z 6 2-[1-[2-(4,4-Dimethylcyclohexyl)-6- methyl-4-oxo-chromen-8- yl]ethylamino]benzoicacid

434 [M + H]⁺ 7 2-[1-[6-Methyl-4-oxo-2-(1- phenylcyclopropyl)chromen-8-yl]ethylamino]benzoic acid; 2,2,2-trifluoroacetic acid

440 [M + H]⁺

Example 8 and Example 9:2-[1-(2-Cyclohexyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid,Isomer 1 and Isomer 2

2-[1-(2-Cyclohexyl-6-methyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid(0.06 g, 0.15 mmol) was separated by reversed phase chromatography usinga Phenomenex Gemini-NX C18 column (75×30 mm; 3 um) eluted with 41% to81% acetonitrile in water (with 0.225% TFA) to give Isomer 1 (17.2 mg,29%) and Isomer 2 (16.7 mg, 28%) as white solids. MS ES+ m/z 406 [M+H]⁺.

The following compounds in Table 10 were made in a similar way asdescribed for Example 8 and Example 9.

TABLE 10 Example MS ES+ # Chemical Name Structure m/z  10^(a)2-[1-[2-(4,4- Dimethylcyclohexyl)-6- methyl-4-oxo-chromen-8-yl]ethylamino]benzoic acid, Isomer 1

434 [M + H]⁺  11^(a) 2-[1-[2-(4,4- Dimethylcyclohexyl)-6-methyl-4-oxo-chromen-8- yl]ethylamino]benzoic acid, Isomer 2

434 [M + H]⁺  12^(b) 2-[1-(2-Cyclohexyl-4-oxo- chromen-8-yl)ethylamino]benzoic acid, Isomer 1

392 [M + H]⁺  13^(b) 2-[1-(2-Cyclohexyl-4-oxo- chromen-8-yl)ethylamino]benzoic acid, Isomer 2

392 [M + H]⁺ 14^(c) 2-[1-[2-(4,4- Difluorocyclohexyl)-6-methyl-4-oxo-chromen-8- yl]ethylamino]benzoic acid, Isomer 1

442 [M + H]⁺ 15^(c) 2-[1-[2-(4,4- Difluorocyclohexyl)-6-methyl-4-oxo-chromen-8- yl]ethylamino]benzoic acid, Isomer 2

442 [M + H]⁺ 16^(d) 2-[1-[2-(4,4- Difluorocyclohexyl)-3,6-dimethyl-4-oxo-chromen-8- yl]ethylamino]benzoic acid, Isomer 1

456 [M + H]⁺ 17^(d) 2-[1-[2-(4,4- Difluorocyclohexyl)-3,6-dimethyl-4-oxo-chromen-8- yl]ethylamino]benzoic acid, Isomer 2

456 [M + H]⁺ 18^(e) 2-[1-(2-Indan-2-yl-6-methyl- 4-oxo-chromen-8-yl)ethylamino]benzoic acid, Isomer 1

440 [M + H]⁺ 19^(e) 2-[1-(2-Indan-2-yl-6-methyl- 4-oxo-chromen-8-yl)ethylamino]benzoic acid, Isomer 2

440 [M + H]⁺ 21^(f) 2-[1-(2-Indan-2-yl-3,6- dimethyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid, Isomer 1

454 [M + H]⁺ 22^(f) 2-[1-(2-Indan-2-yl-3,6- dimethyl-4-oxo-chromen-8-yl)ethylamino]benzoic acid, Isomer 2

454 [M + H]⁺ ^(a)Compounds separated using a Daicel Chiralpak AD-H (250× 30 mm; 10 um) column eluted with 25% EtOH (with 0.1% NH4OH) in CO₂.^(b)Compounds separated using a Daicel Chiralcel OJ (250 × 30 mm; 10 um)column eluted with 20% MeOH (with 0.1% NH₄OH) in CO₂. ^(c)Compoundsseparated using a Daicel Chiralpak AS (250 × 30 mm; 10 um) column elutedwith 45% EtOH (with 0.1% NH₄OH) in CO₂. ^(d)Compounds separated using an(S, S)Whelk-O1 (250 × 30 mm, 5 um) column eluted with 40% EtOH (with0.1% NH₄OH) in CO₂. ^(e)Compounds separated using a Daicel Chiralpak AS(250 × 30 mm; 10 um) column eluted with 40% EtOH (with 0.1% NH₄OH) inCO₂. ^(f)Compounds separated using a Daicel Chiralcel OD (250 × 30 mm;10 um) column eluted with 50% MeOH (with 0.1% NH₄OH) in CO₂.

PI3K-Alpha kinase (PIK3CA) activity, wild-type and H1047R mutant anddetermining IC50 values for inhibitors

Recombinant, catalytically active human full length PIK3KA Wild-type andH1047R mutant were purchased as 1:1 complex of N-terminal 6× his taggedp110α (catalytic) and untagged p85α (regulatory subunit) from EMDMillipore Sigma (cat. no. 14-602M and 14-792M, respectively). PIP2diC8(Avanti Polar Lipids Inc., cat. no. 850185) or Soy PI (Avanti PolarLipids Inc., cat. No. 840044P) was used as lipid substrate. PIP2diC8 orPI lyophilized powder was dissolved in milliQ water to a concentrationof 1mM just before use. 10 mM stock compounds in DMSO were seriallydiluted 1:3 to generate a 10-point curve and plated using an acousticliquid handler system (Echo 550 series instrument, Labcyte). A 10×intermediate compound plate (200 uM starting compound concentration and10% DMSO) was prepared before starting the reaction. A typical reactionmixture (50 uL) comprised 40 mM HEPES buffer, pH 7.4, 25 mM MgCl₂, 0.01%v/v triton-X-100, 1% v/v DMSO, 20 mM NaCl, 1-5 nM WT or H1047R PI3Kprotein, 20 uM ATP, and 50 uM PIP2diC8 or Soy PI. 1% DMSO buffer alonewithout test compound was employed as MAX control (full activity in theabsence of any inhibitor), and no enzyme control was used to determinethe level of background Adenosine 5′-diphosphate (ADP) (MIN control).First, Wild-type (WT) and H1047R mutant protein in kinase buffer withall components except ATP were incubated with or without compound at 27°C. for lh. After the pre-incubation, the reaction was initiated by theaddition of 20 uL of 50uM ATP (20 uM final concentration). The reactionwas allowed to proceed until about 10% conversion of ATP (2 uM ADP) at27° C. After that time, 5 uL of reaction was mixed with 5 uL ofADP-Kinase Glo Reagent (ADP-Glo Kinase assay kit, Promega cat. no.V9102) supplemented with MgCl₂ 10 mM to stop the reaction and depletethe remaining ATP for 40 min at room temperature. Then, 10 uL of KinaseDetection Reagent (ADP-Glo Kinase assay kit, Promega cat. no. V9102) wasadded to simultaneously convert ADP to ATP and allow the newlysynthesized ATP to be measured using a luciferase/luciferin reaction.After 30 min at room temperature the light generated was measured usinga luminometer (EnVision plate reader, Perkin Elmer). Process datathrough Genedata-Screener tool. Relative IC50 values are determinedusing luminescence units by calculating percent inhibition with respectto on-plate “MIN” and “MAX” controls. Data was analyzed using a4-parameter nonlinear logistic equation (four-parameter logisticconcentration-response curve):

Y=bot+[(top−bot)/1+(x/IC50)slope]

where Y=% inhibition, X=concentration yielding y% inhibition,Bottom=minimum value of y attained by curve, Top=maximum value of yattained by curve and Slope=steepness of curve at IC50.

% Inh=[(median Max−x/median Max−median Min)]·100

IC50: concentration of compound that reduces a given response (ligandbinding, enzyme response) by 50%. IC50 relative: concentration givinghalf the compound's maximum response.

For IC₅₀ values shown in Table A, “A” means IC₅₀<0.5 μM; “B” means IC₅₀ranging between 0.5 μM and 1.0 μM; “C” means IC₅₀ ranging between 1 μMand 5 μM; “D” means IC₅₀ ranging between 5 μM and 10 μM; “E” meansIC₅₀>10 μM.

TABLE A PI3K-α (PIK3CA) Biochemical IC₅₀ of PI3K wild-type (WT) andH1047R mutant, using Soy PI lipid substrate IC₅₀ IC₅₀ Example # H1047RWT  7 A E  8¹ C E  9¹ A A  10¹ A C  11¹ E E  12¹ E E 13 A E 14 E E 15 AE 16 A B 17 E E 18 C E 19 A C 21 A C 22 E E ¹PIP2diC8 lipid substrate*For Example 9, IC₅₀ WT/IC₅₀ H1047R = 5.5

1. A compound of the Formula:

or pharmaceutically acceptable salt thereof, wherein: R is —H or C₁-C₃alkyl; is a group of the formula:

R₂ is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, eachoptionally substituted with one to three R10 substituents, or R₂ is agroup of the formula:

R₃ is —H, halogen, —CN, C₁-C₆ alkyl C₁-C₆ haloalkyl, C₃-C₅ cycloalkyl, aheterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatomsindependently selected from N, O, or S, or a heteroaryl of 5 ring atomscontaining 1, 2, or 3 ring heteroatoms independently selected from N, O,or S; each of R₄, R₅ and R₆ is independently —H, halogen, C₁-C₆ alkyl orC₁-C₆ haloalkyl; R₇ is —CN, C₁-C₆ alkyl or C₁-C₆ haloalkyl; R₈ is —H orC₁-C₆ alkyl; each R₉ is independently —H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₃-C₅ cycloalkyl; each R₁₀ is independently—H, —CN, halogen, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,—SO₂R₁₁, —CONR₁₁R₁₁, —NR₁₁R₁₁, —NR₁₁—CO₂R₁₁, —OH, an optionallysubstituted C₁-C₆ alkyl, an optionally substituted C₂-C₆ alkenyl, anoptionally substituted C₂-C₆ alkynyl, an optionally substituted C₃-C₅cycloalkyl, an optionally substituted heterocycle selected frompyrrolidine, pyrrolidinone, piperidine or morpholine, an optionallysubstituted phenyl, an optionally substituted 1,3-benzodioxole, anoptionally substituted 2,3-dihydro-1,4-benzodioxine or an optionallysubstituted heteroaryl selected from pyrazole, isoxazole, isothiazole,imidazole, oxazole, or thiazole; wherein the optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl is each optionallysubstituted with a —CN, —OH, oxetanyl, or C₁-C₃ alkoxy; the optionallysubstituted C₃-C₅ cycloalkyl, phenyl, 1,3-benzodioxole,2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl is eachoptionally substituted with one to three substituents each independentlyselected from halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, C₁-C₃ alkoxy, C₁-C₃haloalkoxy, —SO₂R₁₁, —NR₁₁R₁₁, —OH or —CN; and each R₁₁ is independently—H or C₁-C₃ alkyl.
 2. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, having the Formula:


3. The compound of claim 1, or pharmaceutically acceptable salt thereof,having the Formula:


4. The compound of claim 1, or pharmaceutically acceptable salt thereof,wherein R is —H.
 5. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein R₁ is a group of the formula:


6. (canceled)
 7. The compound of claim 1, or pharmaceutically acceptablesalt thereof, wherein R₉ is —H, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl,or C₃-C₅ cycloalkyl.
 8. (canceled)
 9. The compound of claim 1, orpharmaceutically acceptable salt thereof, wherein R₃ is —H, —CN, C₁-C₆alkyl, or C₁-C₆ haloalkyl. 10.-13. (canceled)
 14. The compound of claim1, or pharmaceutically acceptable salt thereof, wherein R₄ is —H orhalogen.
 15. (canceled)
 16. The compound of claim 1, or pharmaceuticallyacceptable salt thereof, wherein R₅ is —H, halogen, C₁-C₃ alkyl or C₁-C₃haloalkyl.
 17. The compound of claim 1, or pharmaceutically acceptablesalt thereof, wherein R₆ is —H or halogen.
 18. The compound of claim 1,or pharmaceutically acceptable salt thereof, wherein R₇ is —CN, C₁-C₃alkyl or C₁-C₃ haloalkyl.
 19. (canceled)
 20. (canceled)
 21. The compoundof claim 1, or pharmaceutically acceptable salt thereof, wherein R₈ isH.
 22. The compound claim 1 or pharmaceutically acceptable salt thereof,wherein R₂ is

wherein each R₁₀ is independently —H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl.
 23. The compound of claim 22, or pharmaceutically acceptablesalt thereof, wherein each R₁₀ is independently —H, halogen, or C₁-C₃alkyl.
 24. The compound of claim 23, or pharmaceutically acceptable saltthereof, wherein each R₁₀ is independently —H, fluoro, or methyl. 25.The compound of claim 1 selected from:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim1 selected from:

or a pharmaceutically acceptable salt thereof.
 27. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 28.A method of treating a disease or disorder associated with modulation ofphosphoinositide 3-kinase (PI3K), comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 29. The methodof claim 28, wherein the PI3K is PI3Kα.
 30. The method of claim 29,wherein the PI3K associated with the disease or disorder has a H1047Rmutation.
 31. The method of claim 28, wherein the disease or disorder isa cancer.
 32. The method of claim 31, wherein the cancer is endometrialcancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer,lung cancer, ovarian cancer, skin cancer, head and neck cancer, breastcancer, brain cancer, or prostate cancer.
 33. The method of claim 28,wherein the disease or disorder is CLOVES syndrome (congenitallipomatous overgrowth, vascular malformations, epidermal naevi,scoliosis/skeletal and spinal syndrome), or PIK3CA-related overgrowthsyndrome (PROS).
 34. A method of inhibiting phosphoinositide 3-kinase(PI3K), comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 35. A method of treatingcancer or a disorder, the method comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 36. The methodof claim 35, wherein the cancer is endometrial cancer, gastric cancer,leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovariancancer, skin cancer, head and neck cancer, breast cancer, brain cancer,or prostate cancer.
 37. The method of claim 35, wherein the disorder isCLOVES syndrome (congenital lipomatous overgrowth, vascularmalformations, epidermal naevi, scoliosis/skeletal and spinal syndrome)or PIK3CA-related overgrowth syndrome (PROS). 38.-46. (canceled)